In humans, acute retinal necrosis (ARN) is a relatively rare syndrome that has been shown to be caused by at least three members of the human herpesvirus family - HSV-1, HSV-2 and VZV. Although no animal model has absolute fidelity to its human counterpart, the mouse model of ARN which is observed in the retina of the uninoculated eye following inoculation of HSV-1 into one anterior chamber has been used to provide information that may aid in our understanding of the pathogenesis of this disease in humans. Three specific aims are proposed to continue to study the pathogenesis of virus infection of the eye and brain following uniocular anterior chamber inoculation. Studies to address the first aim will use the mouse model of ARN to determine the role of TNF-a in preventing virus infection of the optic nerve and retina of the injected following uniocular anterior chamber inoculation of the KOS strain of HSV-1. Studies to address the second specific aim will define the non-T cell contributions to destruction of the retina of the uninoculated eye in HSV-1 infected BALB/c mice. Studies to address the third aim will use ganglia collected from human donors to determine the frequency of autonomic and sensory ganglia (trigeminal, ciliary, pterygo-palatine and superior cervical) that are positive for HSV-1, HSV-2 and/or VZV. These studies will begin explore the idea that there are additional sites of herpevirus latency besides the trigeminal ganglion and that development of ARN in human patents may be due to reactivation of one of the herpesvirus from a ganglion with direct or indirect connections to the optic nerve and retina. Taken together, the studies proposed in this application will provide new information about factors, such as TNF-a, that control virus infection in the brain and about other modulators that increase the magnitude of retinal damage during HSV-1 infection. Identification of ganglia where the neurotropic herpesviruses are latent in humans may aid in development of targeted therapies to prevent virus from reactivating or from spreading from these sites to the optic nerve and retina once reactivation has occurred.